JPS6230769A - Pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:A pyridazinone derivative expressed by formula I [R1 is H, methyl, 3-6C alkenyl, 5-6C cycloalkyl, benzyl, phenyl, etc.; R2 is Cl or Br; Y1 and Y2 are H, 1-5C alkyl, 2-8C alkenyl, halogen, OR5 (R5 is H, 1-8C akyl, etc.), etc.; Y3 is 1-5C alkyl, 2-8C alkenyl, halogen, OR5, etc.] and salt thereof. EXAMPLE:4-Chloro-5-(3-methoxybenzylamino)-2-cyclopentyl-3(2H)pyridazin one. USE:With antagonism to chemical transmitters causing contraction of bronchial smooth muscles, etc., and useful as an antiallergic agent. PREPARATION:A compound expressed by formula II (Z is Cl or Br) is reacted with a benzylamine derivative expressed by formula III, as necessary, in the presence of a dehydrohalogenating agent in an inert solvent to afford the aimed compound expressed by formula I.

Description

[Detailed Description of the Invention] The present invention relates to a chemical mediator that causes contraction of bronchial smooth muscle, etc. Slow reacting 5ubstance
of anaphy-.

3 (2+1
) Pyridazinone derivative, method for producing the same, and 3() of the present invention
2H) Pharmaceutical compositions containing pyridazinone derivatives.

5R3-A is considered to be the main causative agent of immediate allergies such as bronchial asthma and allergic rhinitis.
Drugs that suppress the pharmacological action of 3-A, i.e., 5R3-A
Antagonists are expected to be useful antiallergic agents.

However, there are few drugs that antagonize 5R3-A, and to date, no examples of practical use have been reported.

Examples of compounds similar to the compounds of the present invention include (a)
Chemical Abstract
ract. A group (3 to 8 carbon atoms),
There is a description of a 3(2H) pyridazinone derivative in which the 4th position is a chlorine atom or a bromine atom and the 5th position is a benzylamino group. However, there are no examples corresponding to the compounds of the present invention in document (a), and furthermore, the use of the compounds described in document (a) is limited only to herbicides, and there is no description of medicinal uses or pharmaceutical activity. do not have.

Similarly, as an example of a compound similar to the compound of the present invention, (b) Chemical Abstract
Act, 62.2773 b), Pretin Société des Hiemis France (Bull, Sac,
Chim.

France, 1964 (9) P2124-32), 3(2F(
) There is a description of pyridazinones, but this document (b) does not include any examples corresponding to the compounds of the present invention, and furthermore, this document (b) does not include any description of pharmaceutical uses or pharmaceutical activities.

Similarly, as an example of a compound similar to the compound of the present invention (C)
German Patent Publication No. 167016.9 (1970,
11,5 published) (hereinafter referred to as Document (C)), the 2nd position is a hydrogen atom, and the aliphatic
), cycloaltph
atic) or araliph
atic), or aromatic (aroIWat
ic) group, the 4th position is substituted with a chlorine atom or a bromine atom, and the 5th position is substituted with an aralkylamino group, but this document (c) describes these pyridazinones. Synthesis method of pyridazinones containing compounds, agricultural chemical uses.

There are only descriptions of its use as an intermediate for medicines and dyes, and as an intermediate for various compounds. However, there is no description of the pharmaceutical activity of these compounds, no examples of these compounds, and no specific examples of these compounds.

(Hereinafter, blank) When we searched and synthesized compounds, we also found the following general formula (1
It has been found that 3(2H)pyricdinone and its pharmaceutically acceptable salts represented by ) are compounds that exhibit anti-5R3-A activity and can be used as active ingredients of anti-allergic agents.

(In the formula, Ro is a hydrogen atom, a methyl group, a carbon number of 3 to 6
alkenyl group, cycloalkyl group having 5 or 6 carbon atoms, benzyl group, phenyl group.

-(Clh)m-COJi (Ri means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, m means an integer of 1 to 4), -(CHz)n-^ [A
means OH or -N(R4)2 (R means an alkyl group having 1 to 3 carbon atoms), and n means an integer of 2 to 6. ] or -CIl□CF3: R2 means a chlorine atom or a bromine atom; Yl+
Y2 are the same or different and are each a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a halogen atom, -0Rs (Rs is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or )]. -COzR6 (R6 is hydrogen atom, carbon number 1
5 to 5 alkyl groups. ) , -N(Ry)
z(Rt means an alkyl group having 1 to 4 carbon atoms.

) or -3RB (RII means an alkyl group having 1 to 4 carbon atoms); Y represents 1 to 5 carbon atoms;
an alkyl group, an alkenyl group having 2 to 8 carbon atoms;

Halogen atom, -0Rs (Rs has the same meaning as above), -COJb (Ri has the same meaning as above), -N(Ry)t (Rt has the same meaning as above) ) or −5Rs (R has the same meaning as in the above explanation). ) R6R2, Y+, "it" and Y3 of the above general formula (I) will be further explained using specific examples.
) is not limited by these specific examples.

(Note: In the substituents below, n is normal and i is iso.

sec means secondary and 1t means tertiary. )
R1 is a hydrogen atom, a methyl group, or an allyl group.

2-butenyl group, 2-pentenyl group, 2-hexenyl group, cyclopentyl group, cyclohexyl group.

Benzyl group, phenyl group, carboxymethyl group.

2-carboxyethyl group, 3-carboxypropyl group,
4-carboxybutyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, n-propoxycarbonylmethyl group, i-propoxycarbonylmethyl group, n
-butoxycarbonylmethyl group, i-butoxycarbonylmethyl group, t-butoxycarbonylmethyl group, n-pentyloxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group.

2-n-propoxycarbonylethyl group, 2-1-propoxycarbonylethyl group, 2-n-butoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-
Ethoxycarbonylpropyl group, 3-n-propoxycarbonylpropyl group.

3-i-propoxycarbonylpropyl group, 4-medoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group.

5-hydroxypentyl group, 6-hydroxyhexyl group, 2-dimethylaminoethyl group, 2-diethylaminoethyl group, 2-di(n-propyl)aminoethyl group, 3
-dimethylaminopropyl group.

3-diethylaminopropyl group, 3-di(n-propyl)aminopropyl group, 4-dimethylaminobutyl group, 5-dimethylaminopentyl group, and 2.2.2-
1-Lifluoroethyl group is exemplified, chlorine atom and bromine atom are exemplified for R2, y+ and Y2 are the same or different from each other, and for each, hydrogen atom, methyl group, ethyl group, n-propyl5. t-propyl5. n-butyl group, i-butyl group, 5ec-butyl group, n-pentyl group, i-pentyl group, vinyl group, -
propenyl ll, l-phthynyl group, 1-pentenyl i,
l-hexenyl group, nihebutenyl group, ■-octenyl group, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxy group, methoxy group, ethoxy group.

n-propoxy group, i-propoxy group, n-butoxy group, i-butoxyi, 5ec-butoxy group, n-pentyloxy group, n-hexyloxy group, n-hebutyloxy group, n-octyloxy group, benzyl Oxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-
phenylbutyloxy group, methylthio group, ethylthio group, n-propylthio group, n-butylthio group, i-butylthio group, carboxy group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group.

i-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, n-pentyloxycarbonyl group, dimethylamino group, diethylamino group, di(n-propyl)amino group and di(n-butyl)
Amino groups are exemplified, and for Y3, methyl group, ethyl group, n-propyl group, i~propyl group, n-butyl group,
i-butyl 5,5ec-phthyl group, n-pentyl L
i-pentyl group, vinyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, 1-hexenyl group.

1-hebutenyl group, 1-octenyl group, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxy group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy5. n-pentyloxy group, n-hexyloxy group, n-hebutyloxy group, n-octyloxy group, benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group 5
Methylthio group, ethylthio group, n-propylthio group, n
-butylthio group, i-butylthio group, carboxy group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n
-butoxycarbonyl group, i-butoxycarbonyl group,
n-pentyloxycarbonyl group, dimethylamino group,
Examples include diethylamino group, di(n-propyl)amino group and di(n-butyl)amino group.

Next, the method for producing the compound of the present invention will be explained. Compound of the present invention (I
) can be produced according to the following reaction formula.

Reaction formula (11% Formula% ([[) or its salt (hereinafter, blank) (In the reaction formula, R,, R1+ Yl+ Y, and Y
has the same meaning as in the above description of general formula (I), and Z means a chlorine atom or a bromine atom. ) That is, the 3(2H) pyridazinone compound (n), which is one of the raw materials, and the benzylamine l'A'11 form (In) or its acid salt are inactivated in the presence of a hydrogen halide removing agent as necessary. It can be produced by reacting in a suitable solvent.

? Examples of solvents include ether solvents (e.g. diethyl ether, isopropyl ether, tetrahydrofuran, 1,
4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.).

Dimethyl sulfoxide, alcohol solvents (e.g. methanol, ethanol, i-propanol, etc.), hydrocarbon solvents (e.g. toluene, benzene, etc.), ketone solvents (e.g. acetone, methyl ethyl ketone, etc.), organic amine solvents (pyridine, etc.).

trialkylamines) or water, or a mixed solvent thereof can be used.

In the above reaction, when R2 is a chlorine atom or a bromine atom, the compound of the present invention (in addition to the isomer thereof, the general formula in which a benzylamino group is substituted at the 5-position (in the formula R +, Z ,
Y+, Yz, Ys have the same meaning as above,
) are produced as by-products, but (1) and (IV)
The production rate mainly depends on the polarity of the solvent used. i.e. water, alcohol.

When a highly polar solvent such as ether, amide, or dimethyl sulfoxide is used, the production rate of the compound (I) of the present invention increases, and conversely, the use of a highly polar solvent such as ether, amide, or dimethyl sulfoxide increases the production rate of the compound (I) of the present invention;
When using , the production rate of (IV) tends to increase.

Therefore, in order to efficiently obtain the compound (I) of the present invention, it is more preferable to use the above-mentioned highly polar solvents or, if necessary, to use a mixed solvent of water and an organic solvent.

As a method for separating and purifying (1) from a mixture, the objective can be easily achieved by crystallization or column chromatography using silica gel.

When using a hydrogen halide remover, an inorganic base (
For example, potassium carbonate 9 sodium carbonate.

sodium bicarbonate) and organic bases (e.g. N,
Examples include tertiary amines such as N-dimethylaniline, N,N-diethylaniline, trimethylamine, and triethylamine, and aromatic amines such as pyridine. Additionally, a quaternary amine salt (eg, triethylbenzylammonium chloride) can be added to the reaction system as a phase transfer catalyst.

The reaction temperature can range from 10°C to the boiling point of the solvent used in the reaction.

Although the molar ratio of the raw materials can be set arbitrarily, the benzylamine derivative represented by the general formula (III) is used in an amount of 1 to 5 times the molar amount, preferably 1 to 3 times the molar amount of the pyridazinone derivative represented by the general formula (n). do.

The above-mentioned 3(2H) pyridazinone compound (n), which is one of the raw materials, is produced by reaction formula (2) (Advances in Heterocyclic Chemistry (Advancesin H
eterocyclic chemistry, Vo
l 9 * P, 257 (1968))) or reaction formula (3) (Chemical Abstract (Chemi
cal Abstract, 62+ 2772g)).

(Hereafter, blank space) Reaction formula (2) or its salt (II) Reaction formula (3) (In reaction formulas (2) and (3), R,, R2 and Z are the same as in the above general formula (I). meaning, R1
1 means an alkyl group, a benzyl group, an alkenyl group, or an alkyl group substituted with a hydroxyl group, an amino group, an ester group, a halogen atom, etc., and Hal means a chlorine atom, a bromine atom, or an iodine atom. ) The method shown by reaction formula (2) shows a general method for producing pyridazinone compounds in general represented by the general formula (n), which is a ring-closing reaction between hydrazines or their acid salts and mucochloric acid or mucobromic acid. On the other hand, the method shown by reaction formula (3) is a separate method for synthesizing the compound represented by the general formula (■') having a substituent at the 2-position in the compound represented by the general formula (II). i.e. 4.5- (dichloro or bromo)
-3(2H)pyridazinone and general formula Rx-Hal (R8
and Ha7! has the same meaning as above. ) is reacted with a halide represented by formula (■') to produce a compound represented by general formula (■'). In the production of the compound represented by general formula (II), methods (2) and (3) can be used as appropriate. Method (2) is advantageous in terms of reaction yield and operability, but when the raw material hydrazine is not readily available as a commercial product or cannot be produced economically, method (3) is preferred. It is generally advantageous to use the method.

Regarding the other raw material, benzylamines represented by the general formula [in the formula, Y+, Yz, and Yz have the same meanings as described above], those that are not commercially available can be used, for example, as shown in Scheme 1. Generally, it can be produced according to known benzylamine production methods.

(Hereinafter, blank space) Scheme 1 Method for producing various benzylamines (A) (In the formula, R means a hydrogen atom or an alkyl group (B) (C) Method (A) uses the corresponding aldehyde as a starting material and converts it into a hydroxyamine. The desired product can be obtained by treating the intermediate aldoxime obtained by reacting the intermediate aldoxime with alkoxyamine, (B) the corresponding nitrile as the starting material, and (C) the corresponding amide as the starting material, with various reducing agents. This is a method to obtain benzylamine.

Methods (A) to (C) can be appropriately selected using available commercial products or starting materials derived therefrom. Examples of the reduction method include (a) a method using (a) Raney nickel and fuker-aluminum alloy in the presence of an alkali metal hydroxide such as sodium hydroxide; (b) A method using sodium borohydride in the presence of an acid such as acetic acid, trifluoroacetic acid, or Lewis acid is known, but the substituent Yl+Y2+Y of the phenyl nucleus is known.
3 (Yl, Yi, and Y3 have the same meanings as described above) can be used appropriately from the viewpoint of chemical stability. For example, when the substituents Y, Y, Y3 are substituents having an alkyl group, an alkoxy group, etc. that are stable even against relatively strong reducing agents, the reduction method (a) is suitable, and Unstable substituents such as halogen,
In the case of substituents having olefins, esters, amides, etc., the (K) reduction method, which is a relatively mild reduction method, is suitable.

In general, benzylamines combine with carbon dioxide gas in the air to form carbonates, so it is often more convenient to isolate them in the form of acid salts (e.g. hydrochlorides, sulfates, etc.) . It can also be used as a hydrochloride in the reaction with 4,5-di(chloro or promo)-3(2H)pyridazinone.

In addition, in the compound (1) of the present invention, the substituent YI+
1.2 or 3 of Yi Y3 are -CO,R.

(R6 represents an alkyl group having 1 to 5 carbon atoms), a compound having a corresponding carboxyl group or a salt thereof is used as a deoxidizing agent (for example, a carbonate such as sodium hydroxide, potassium hydroxide, potassium, sodium, etc.). monobicarbonate or organic amine)), the general formula (R60)zsO4(
Rh represents an alkyl group having 1 to 5 carbon atoms. ) or esterified with a dialkyl sulfate ester represented by -i formula R,01l (R, has the same meaning as above).
An alcohol represented by an acid catalyst (e.g. sulfuric acid,
It can also be easily obtained by esterification by reaction in the presence of hydrochloric acid (hydrochloric acid, etc.).

Examples of the compounds of the present invention include those listed in the following table, in addition to the compounds described in the Examples relating to the production method described later. (In the following compounds, n is normal, i
stands for iso, cyc stands for cyclo, Me stands for methyl group, Et
is an ethyl group, Pr is a propyl group, Bu is a butyl group, Pen is a pentyl group, flax is a hexyl group, l
1ep means heptyl group, Oct means octyl group, and ph means phenyl group. ) Administrative forms of the compound of the present invention include injections (subcutaneous, intravenous, intramuscular, and intraperitoneal injection);
Parenteral administration via ointments, suppositories, 1 aerosol, etc., or tablets.

Capsules, granules, pills, syrups, liquids.

Oral administration using emulsions, suspensions, etc. can be mentioned.

The above pharmaceutical or veterinary composition containing the compound of the present invention contains about 0% of the compound of the present invention, based on the weight of the total composition.
．． 1 to 99.5%, preferably about 0.5 to 95%.

In addition to the compounds of the invention or compositions containing the compounds of the invention, other pharmaceutically or veterinary active compounds can be included. Additionally, these compositions can contain more than one compound of the invention.

Although the clinical dosage of the compound of the present invention varies depending on the age, body weight, sensitivity of the patient, severity of symptoms, etc., the usually effective dosage is 0.003 to 1.5 g per day for adults, preferably 0.01 g.
It is about 0.6g. However, amounts outside the above ranges can be used if desired.

The compounds of this invention are formulated for administration by conventional pharmaceutical means.

That is, tablets, capsules, and granules for oral administration.

The emulsion contains excipients (2) such as white sugar, lactose, glucose, starch, mannitol; binder (1) such as syrup.

Gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegrants 2 such as starch, carboxymethylcellulose or its calcium salts, microcrystalline cellulose, polyethylene glycol; lubricants 1 such as talc, magnesium or calcium stearate, silica; wetting Agent 1 is prepared using, for example, sodium laurate, glycerol, and the like. Injections, solutions, emulsions, suspensions, syrups and aerosols can be prepared using a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1
, 3-butylene glycol, polyethylene glycol;
Surfactant 2 For example, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; Suspending agent 1 For example, carboxymethyl sodium salt, cellulose derivatives such as methyl cellulose, Natural rubbers such as tragacanth and gum arabic;
Preservatives 2 are prepared using, for example, esters of paraoxybenzoic acid, benzalkonium chloride, sorbate, and the like. Suppositories are prepared using, for example, polyethylene glycol, lanolin, coconut oil, and the like.

The main body of 5RS-A, which is an important mechanism for bronchoconstriction in immediate-type allergies such as allergic asthma, is leukotriene Ca (leukotriene C4).
) (hereinafter referred to as LTC), leukotriene D4 (
leukotriene D4) (hereinafter referred to as LTD4)
That's what it means. ) etc. has already been clarified. Therefore, the test method for determining the antagonistic activity against 5R3-A is as follows: (1) Examine the antagonistic activity against 5RS-^ obtained from sensitized guinea pigs.

■ Examine the antagonism to LTC.

■ Examine the antagonism to LTD4.

The activity can be examined using any of the methods ① to ② above.

The present inventors investigated 5RS-A antagonistic activity using the methods ① to ① above.

The test method and test results are described below.

(1) Test method for antiallergic activity (i) LTC and LTD in guinea pig tracheal muscle specimens.

A spiral specimen of tracheal muscle isolated from a guinea pig (one male weighing 300 to 400 g) was prepared, and L was determined using the Magnus method.
Antagonistic activity against TC4 and LTD was tested.

The tracheal muscle specimen was suspended in Tyrode's solution kept at 37°C.
After applying a load of Ig and first contracting with histamine (concentration 100 μmol), contractions were obtained by LTC4 and LTD (concentration 2 × 10-” g/mj). Dissolve, LTC
, and 10-5 g/ml or 10-''g/1all CO, 2% dimethyl sulfoxide solution) 5 minutes before administration of LTD4.
In addition to h), the contraction was compared with that of the control.

The control and evaluation tests were conducted using different tracheal muscle specimens obtained from the same guinea pig. Then, all LTC and LTD reactions were converted to the histamine (concentration 100 μmol) reaction in the same sample, and then LTC and LTD were converted as follows.
The antagonism rate (%) of C4 and LTD4 was determined.

(ii) LTD4 antagonistic activity in guinea pig tracheal muscle specimen A spiral specimen of tracheal muscle isolated from a guinea pig (M10 weight 300-400 g) was prepared and tested for LTD4 antagonistic activity using the Magnus method.

The tracheal muscle specimen was kept at 37°C and suspended in Tyrode's solution containing 5 μmol of indomethacin, and a load of 1 g was applied.
First, after contracting with histamine (concentration 100 μmol),
The test compound was dissolved in 100% dimethyl sulfoxide and placed in an organ bath (4 doses, 3 doses, 3 doses of LTD).
) and compared with control contraction.

The control and evaluation tests were conducted using different tracheal muscle specimens obtained from the same guinea pig. and all LTD4 responses were histamine (concentration 100 μmol) in the same specimen.
After converting into the reaction of LTD. The antagonism rate (%) was calculated.

(iii) Anaphylaxis in passively sensitized guinea pigs
Rabbit anti-esogalpmin (EA) serum (Cappl) was administered into the pudendal vein of guinea pigs (body weight 350-450 g).
0.125 m2 (manufactured by E Company) was administered for passive sensitization. One to two days after sensitization, the anaphylactic airway constriction that appears due to antigen administration was induced, and the in situ activity against it was investigated. Airway constriction is caused by Konze & Roessle
r(Arch, E!xp, Path, Pharma
ko, 195+7L (1940)). Urethane (administration ii 1.5) to sensitized guinea pigs
g/kg) was administered intraperitoneally to anesthetize the animal, and a cannula was inserted and fixed into the trachea, and then a small animal respirator (manufactured by Shinano Seisakusho) and a differential pressure transducer (Nihon Kohden TP-602T) were connected.

Artificial respiration: 50 strokes/min, 4.5 ml
EA (0, 2 or 10 cm/kg) was administered through the jugular vein under positive pressure at a rate of
The o amount was recorded on a polygraph (Nihon Kohden Wl-681C) via a transducer.

After the experiment was completed, the value when the trachea was completely occluded with Kosohel was defined as the maximum contraction (<100%), and the results were expressed as a percentage of this value.

In addition, indomethacin (1,0■/1qr), birilamine (2,0
nv/kg) and prop, ut/t:l-le(0,
1w) and were administered through the jugular vein, respectively. Test compounds were administered intravenously (i, v,) or orally (P) prior to antigen administration.

o,), and the inhibition (%) of airway constriction was determined as follows.

However, the maximum response % was determined from the highest value of airway contraction within 30 minutes after antigen administration.

The i, v, administration test was conducted in 4 cases, and the p, o, administration test was conducted in 5 to 6 cases, and the inhibition rate was the average value of each.

(iii) - (a) i, v, administration test: The test compound (2 mg/kg) was suspended or dissolved in 3% Tween 80 and administered via the jugular vein 1 minute before administration of EA (dose 10 μ/kg). administered. Control response was 73±9
(Mean±S, D,, n=4), which is FPL-5
It was inhibited by 27% at 57122 mg/kg.

(iii) - (b) ρ, O8 administration test: The test compound was suspended in 5% gum arabic, and EA (administration 10.2
■/kg) Orally administered 2 hours before administration. Control response was 62±6%.

In all tests, FPL-55712 (Faison) was used as a control drug.

(2) Antiallergic activity test results (i) Test compound (concentration 10-'g/mβ) below LTC4 antagonistic activity using guinea pig trachea specimen (7) L
T(.

It showed antagonistic activity. (Based on test method (i)) (ii
) Test compound below LTD4 antagonistic activity using guinea pig trachea specimen (concentration 10-' g/raj!)
showed anti-LTD* antagonistic activity. (Based on test method (i).) (Hereinafter in the margin) (iii) LTD using guinea pig tracheal muscle specimen, test compound with less than antagonistic activity (concentration 10-6 g/mj2)
showed antagonistic activity against LTD. Note that the values marked with * indicate the results based on test method (i), and the other values indicate the results based on test method (ii).

(iv) Effect on anaphylactic airway constriction in passively sensitized guinea pigs (t, v, administration) The effects of the test compound (dose: 2 .mu./kg) are shown below. (Based on test method (i+t)-(a)) (v) Effect on anaphylactic airway constriction in passively sensitized guinea pigs (p, o, administration) The effects of the test compounds are shown below. (Based on test method (iii)-(b).) Oral administration of FPL-55712100/kg had almost no suppressive effect.

B. Acute toxicity test (i)-1 Test method-1 One to two ddY mice (male, 4 weeks old) were used per group, and the mortality rate after 7 days of intraperitoneal administration was shown.

(ii)-1 Test results-1 (i)-2 Test method-2 A group of 3 ddY mice (4 weeks old male) was used to show the mortality rate after 7 days of oral administration.

(ii) -2 Test Results -2 The product was 5R5 in vitro and in vivo.
-8, and its main constituents LTC4,LT
It has significant antagonistic activity against D4. Therefore, the compounds of the present invention can be used as active ingredients in preventive and therapeutic agents for various allergic diseases caused by 5R3-A, such as bronchial asthma, allergic rhinitis, and urticaria.

The present invention will be described below in detail with reference to Examples, but the present invention is not limited to these Examples. Note that the symbols rNMRJ and rMsJ in the Reference Examples or Examples represent [Nuclear Magnetic Resonance Spectrum J] and "Mass Spectrometry", respectively, in the same order. rNMRJ describes only the characteristic absorption, rMsJ
only the parent peak or representative fragment peaks are listed.

In addition, in the explanation of substituents in the text and tables below, Me stands for methyl group, Ct stands for ethyl group, Pr stands for propyl group, nu stands for butyl group, Pen stands for pentyl group, I
leχ is hexyl group - llep is heptyl group, p
h means a phenyl group, n means normal, i means iso, cyc means cyclo, and t means tertiary.

Reference Example 1 3.4-dimethoxybenzylamine hydrochloride 24.06 g of 3.4-dimethoxybenzaldehyde.

Hydroxylamine sulfate 14.28g, sodium hydroxide 7.25g, methanol 300nF! and water 250
ml of the mixture is refluxed for 1 hour under stirring.

After cooling, add 14.5 g of sodium hydroxide and dissolve, then add 40 g of Raney nickel (Ni-A 1 alloy) under water cooling.
Gradually add small amounts. After the addition was completed, the water bath was removed and stirring was continued for 1 hour at room temperature. The reaction mixture is filtered, the methanol from the filtration is distilled off under reduced pressure, and the resulting residue is extracted with diethyl ether.

After washing the extract with saturated saline and drying with sodium sulfate,
The solvent was distilled off to obtain a colorless oil.

NMR (CDCl3)δ: 6.77 (3FI, s
), 3.81.3.80 (3H, s each), 3.75
(211, s), 1.58 (211, s; disappeared by addition of DzO.) The residual oil was diluted with 100 ml of diethyl ether and diluted with 6N HCI! under ice cooling. L4-dioxane solution 25ml 1l
added. The precipitated solid was collected by filtration and washed with ether.
29.36 g of the title compound was obtained as a colorless powder.

Using the same production method as above, 4-i-propyl, 3-ethoxy, 4-ethoxy, 3-n-propoxy, 3-ethoxy-4-methoxy, 3-n-propoxy-4- Methoxy, 3-n-butoxy-4-methoxy.

3-n-pentyloxy-4-methoxy, 3-n-hexyloxy-4-methoxy, 3-n-hebutyloxy-
4-methoxy, 3-phenethyloxy-4-methoxy,
3, 4, 5. - Benzylamines having each substituent of 1-rimethoxy and their hydrochlorides were produced.

Reference Example 2 4-diethylaminobenzylamine hydrochloride 8.80 g of 4-diethylaminobenzaldehyde.

4.59 g of 0-methylhydroxylamine hydrochloride.

A mixture of 11.87 g of pyridine and 80 nl of ethanol was refluxed for 1 hour while stirring. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with benzene. The extract was washed with water (twice) and saturated brine, then dried over sodium sulfate, and the solvent was distilled off to give a pale yellow oil.
10.30 g of methylaldoxime was obtained.

NMR(CDCjl!z)δ: 7.87(IH,s
), 7.34, 6.54 (28° ABq each), 3
．． 85(3)1. s), 3.33 (411, q), 1
．． 15 (6B, t) 7.6 g of sodium borohydride and 200 mj of tetrahydrofuran! 22.8 g of trifluoroacetic acid was added to a suspension of 10 mj of tetrahydrofuran under water-cooling and stirring. A solution dissolved in water was added dropwise over a period of 20 minutes. After the dropwise addition was completed, the water bath was removed, and the reaction solution was left at room temperature for 1 hour. Then, 0.30 g of the O-methylaldoxime obtained above was added, and the reaction was carried out at the same temperature for 1 hour. Reflux for an hour. After cooling, the reaction mixture was cooled with water.
Water was added to destroy excess reducing agent. The residue obtained by distilling off tetrahydrofuran was extracted with dichloromethane, the extract was washed with water and saturated brine, dried over sodium sulfate, the solvent was evaporated, and 6N Hci-t-san solution was added. Add 125ml of ff under water cooling. The mixture was evaporated under reduced pressure and the resulting solid was treated with methanol-ether to yield 11.13 g of the title compound as a colorless powder.

The NMR spectrum of the free amine is shown below.

NMR (CDCj!s) δ: 7.06. 6
．． 56 (2H each, 8Bq), 3.66 (2H1s) +
1.11(6)1. t), 3.27 (4H, q), 1.
55 (2H,s, disappeared by addition of DzO) Using the same production method as above, 3-hydroxy-4-methoxy, 3-benzyloxy, 3-benzyloxy-4-methoxy, 3- Hydroxy-4-methoxy.

Benzylamines having each substituent of 4-methylmercapto and their hydrochlorides were produced.

Reference Example 3 4 (cis-1-hebutenyl)benzylamine hydrochloride A mixture of 1.86 g of trichloroacetic acid and 3 ml of tetrahydrofuran was added dropwise to a mixture of 617 nw of sodium borohydride and 100 ml of tetrahydrofuran while cooling with water and stirring. After the addition was completed, the water bath was removed and the reaction mixture was stirred for 1 hour. Subsequently, 4-cyanobenzaldehyde and triphenyl-n-hexylphosphonium bromide are treated in the presence of n-butyllithium and hexamethylphosphoric triamide in the reaction mixture to produce Wit.
3.09 g of 4-(cis-1-hebutenyl)benzonitrile obtained by subjecting it to a condensation reaction with Tig reagent in tetrahydrofuran to 3 m6 of tetrahydrofuran. The solution was added dropwise and stirred at room temperature for 3 hours. After adding ice chips to decompose the excess reducing agent, the reaction mixture is evaporated and the resulting residue is extracted with benzene. After washing the extract with water, saturated saline, and drying with sodium sulfate,
The solvent was distilled off to obtain a pale yellow oil. Dissolve this product in 80mf of ether, add 6N+1Cf1.4-dioxane solution 31I11 under water cooling, and filter the precipitated solid matter.
Wash with ether to obtain the title compound 3 as a slightly yellow solid.
．． 47 g was obtained.

The NMR spectrum of the free amine is shown below.

NMR (CDCl,) δ: 7.1? (4H,s),
4.33 (111, d, J = 10.8 Hz), 3
．． 78 (2H, s) Reference Example 4 4-chlorobenzylamine hydrochloride Sodium borohydride 7.30 g, 4-chlorobenzamide 6,00 g and 1,4-dioxane 100 m
A mixed solution of 11.58 g of acetic acid and 30 ml of 1,4-dioxane was added dropwise to the mixture of No. 1 over 30 minutes while stirring under water cooling. After the dropwise addition, the reaction solution was stirred and refluxed for 2 hours. After cooling, ice pieces were added little by little to decompose the excess reducing agent, and then the solvent was distilled off under reduced pressure.

The residue was extracted with chloroform, the extract was washed with saturated saline, dried over sodium sulfate, and the solvent was evaporated to about 80II11
It was concentrated to Cool the concentrate on ice, and 6N HCj! 1.
10 ml of 4-dioxane solution was added dropwise.

The precipitated solid was treated with methanol-ether to obtain 3.16 g of the title compound as a colorless powder. The NMR spectrum of the free amine is shown below.

NMR (CDCffi 3) δ: 7.38 (4) 1.
s), 4.16 (2■+s) + 1.55 (211,
s: Disappeared by addition of DzO. ) Reference Example 5 4,5-dichloro-2-allyl-3(2H)pyridazinone 4,5-dichloro-3(28)pyridazinone 16.4
g.

14.5 g of allyl bromide and 60 mj of dimethylformamide! 4.3 g of sodium hydride (55% mineral oil suspension) was added little by little to the mixture at 15-20°C, and the reaction mixture was stirred at 20-25°C for about 2 hours. After cooling, the reaction mixture was poured with 200 ml of cold water. Hexane-benzene (
5:1; V/V). The organic layer was dried and the solvent was distilled off, and the obtained crude crystals were recrystallized from n-hexane to obtain 10.3 g of the title compound. Melting point: 45°C Reference Example 6 4,5-dichloro-2-benzyl-3(2)1)pyridazinone Using the same method as in Reference Example 5, 8.2 g of 4,5-dichloro-3(2H)pyridazinone, benzyl 7.5 g of the title compound was obtained from 6.4 g of chloride, 2.2 g of sodium hydride and 40 ml of dimethylformamide.

Melting point: 86°C (recrystallized from n-hexane) Reference example 7 4.5-dichloro-2-cyclobenzene 3 (28)
Pyridazinone (hereinafter referred to as the margin) Using the same method as Reference Example 5, 4,5-dichloro-3
(2H) 4.5 g of the title compound from 16.5 g of pyridazinone, 22.8 g of cyclopentyl bromide, 4.3 g of sodium hydride and 60 ml of dimethylformamide
I got it.

Melting point 56-57°C (methanol:water = I:10; V/
(Recrystallized from V) Reference Example 8 4.5-dichloro-2-(2,2,2-1-lifluoroethyl)-3(2+1)pyridazinone Using the same method as in Reference Example 5, 4.5- dichloro-3
(2H) Pyridazinone 16.5 g, 2,2.2-
17.9 g of trifluoroethyl bromide, 4.3 g of sodium hydride and 60 mj of dimethylformamide!
15.3 g of the title compound was obtained.

Melting point 62°C (recrystallized from n-hexane) Reference example 9 4.5-dichloro-2-carboxymethyl-3(21(
) Pyridazinone 4.5-dichloro-3(2B) pyridazinone 12.4g
, iodoacetic acid 14.6g, potassium carbonate 20.7g
, and 100 ml of dimethylformamide.
Stirred at 0°C for 4 hours.

After the reaction is completed, the solvent is distilled off, and then a 10% aqueous solution of sodium hydroxide (60 mA) and benzene 100+y/! was added and shaken vigorously to remove the benzene layer, and the aqueous layer was acidified with 10% hydrochloric acid, extracted with 100 ml of ethyl acetate, and dried.

The crude crystals obtained by distilling off the solvent were recrystallized (ethyl acetate:
Ethyl ether: petroleum benzine = l:l:1; V/V
) to obtain 3.26 g of the title compound.

Melting point 175-177°C Reference example 10 4.5-dichloro-2-(2-hydroxyethyl)-3
(211) Pyridazinone 4.5-dichloro-3 (211) Pyridazinone 16.5
g, 15 g of 2-bromotanol, 16 g of potassium carbonate.
5g.

1.5 g of sodium iodide, 60 IIl of dimethylformamide! ! The mixture was stirred at 60°C for 4 hours.

After distilling off the solvent, add 80 ml of ethyl acetate and 80 ml of water.
The mixture was shaken vigorously, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The oil obtained by distilling off the solvent was purified by column chromatography using silica gel (ethyl acetate as a developing agent) to obtain 8.7 g of the title compound as a pale yellow oil.

Reference Example 11 4.5-dichloro-2-(3-hydroxypropyl)-
3(2H) Pyridazinone Using the same method as in Reference Example 10, 4,5-dichloro-
3(21+)pyridazinone 16.5g, 3-bromo1-
Propatool 16.7g, potassium carbonate 16.6g.

An oily substance obtained by reacting a mixture of 1.5 g of sodium iodide and 70 ml of dimethylformamide was purified by column chromatography using silica gel (developing agent: benzene: ethyl acetate = 1:1; V/V) to obtain a pale 13.7 g of the title compound was obtained as a yellow oil.

Reference Example 12 4.5-dichloro-2-(2,2-dimethylaminoethyl)-3(2+1)pyridazinone Using the same method as Reference Example 10, 4.5-dichloro-2-(2,2-dimethylaminoethyl)-3(2+1)pyridazinone
3(211)pyridazinone 41.0g, 2,2-dimethylaminoethyl chloride 40.4g, potassium carbonate 64
．． 5 g of sodium iodide and 80 ml of dimethylformamide were reacted, and the resulting oil was subjected to column chromatography using silica gel (
Developer chloroform: methanol = 5: 1 i V/
V) to give the title compound 7. as a pale yellow oil.
72g was obtained.

Reference example 13 4.5-dichloro-2-(2-(t-butoxycarbonyl)ethyl)-3(21()pyridazinone Reference example 10
Using a method similar to 4,5-dichloro-3(2H)
Pyridazinone 19.3g, 2-(t-butoxycarbonyl)ethylbromide 29.4g, potassium carbonate 19.
3 g of sodium iodide and 60 ml of dimethylformamide were subjected to column chromatography using silica gel (developing agent: benzene: ethyl acetate = 10: 1 iV/V).
to give 8.1 g of the title compound as a pale yellow oil.
I got it.

Exfoliation mold 4-chloro-5-(3-methoxybenzylamino)-2
-cyclopentyl-3(2H)pyridazinone (compound 1
kl) 3-methoxybenzylamine 0.75 g, 4
．． 5-dichloro-2-cyclopentyl~3(2+1)pyridazinone 0.5g, potassium carbonate 0.4g, 1.4-
Dioxane 5m! , 15ml of water! Stir the mixture of 7
Refluxed for an hour.

Water was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was extracted with ethyl acetate. Add the extract to 2% diluted hydrochloric acid and water.

After washing with saturated brine and drying over sodium sulfate, the solvent was distilled off to obtain a pale yellow oil. The product was crystallized from diethyl ether n-hexane to give 250 ml of the title compound as colorless crystals with a melting point of 113-115°C.

NMR (CDC1i) δ: 7.54 (IH, s)4.
53, 4.43 (total of 211. each S) 3.77 (31 (, s), 2.24-1.52 (9tl)
, m) Example 2 4-chloro-5-(3,4-dimethoxyhensylamino)-2-(2-N, N-dimethylaminoethyl)-3
(2+1) Pyridazinone (Compound 8) 4.5-dichloro-2-(2-N,N-dimethylaminoethyl)-3(2+1) Pyridazinone 500■, 3.4
1.29 g of -dimethoxyhensylamine hydrochloride, 1.18 g of potassium carbonate, 6 mff1 of 1,4-dioxane and 18 mρ of water were refluxed for 7 hours with stirring. The 1,4-dioxane was distilled off under pressure, and the residue was extracted with chloroform. After drying the chloroform layer with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Customer solvent: chloroform: methanol - 5:1), and further crystallized from acetone-n-hexane. 270 mg of the title compound was obtained as yellow crystals with a melting point of 180-182°C.

NMR (CDC#,) δ: 7.55 (111,s)
,6.82(311,sL5.04(Ill,brs
) 4.47, 4.37 (total 211. each s), 4.
21 (2H, t), 3.84 (611, s), 2
．． 66 (211, t), 2.25 (611, s).

Mass (m/e): 330 (M+-11cL), 29
6,150.71 (100Z).

Example 3 4-chloro-5-(3-n-pentyloxy-4-methoxybenzylamino)-2-(2-D-butyloxycarbonyl)ethyl l-3(2H)pyridazinone (compound series ○ 4.5 -dichloro-2-(2-(t-butyloxycarbonyl)ethyl)-3(2!+)pyridazinone 1.43
g, 3-n-pentyloxy-4-methoxybenzylamine hydrochloride 3.8 g, potassium carbonate 2.69 g+ 1
．． 25 mA of 4-dioxane and 75 mJ of water with stirring
After refluxing for an hour, 1,4-dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water in that order, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent: benzene: ethyl acetate = 2:1),
1.56 g of the title compound was obtained as a pale yellow viscous substance.

NMR (CDCl2-r) δ: 7.53 (LH, s)
, 6.82 (311, s), 5.18 (III, brs
) 4.48.4.38 (211. each s in total), 4
．． 30-3.80 (411, m), 3.83 (
3H,s), 2.70 (211,s), 2.
00-1.10 (611, m), 1.40 (9tl
, s), 0.93 (311, t).

Mass (m/e): 479 (M”), 3
88.207 (100χ), 137° Example 4 4-chloro-5-(3,4-dimethoxybenzylamino)-2-(carboxymethyl)-3(2+1)pyridazinone (Compound 10) (Hereinafter, blank) 4.5-dichloro-2-carboxymethyl-3 (211
) Pyridazinone 178 mg, 3.4-dimethoxybenzylamine hydrochloride 1.018 g, potassium carbonate 1.1
1g.

A mixture of 2 mff1 of 1.4-dioxane and 20 mff of water was refluxed for 17 hours with stirring. Most of 1,4-dioxane was distilled off under reduced pressure, diluted hydrochloric acid was added to the resulting residue to make pl+ about 2.0, and the mixture was extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain a pale yellow oil.

The residue was mixed with chloroform-methanol (8:1; V/
Elute V)? The pale yellow viscous oil obtained by distilling off the solvent was crystallized from methanol-diethyl ether to give the title compound 11 as colorless crystals with a melting point of 168-171°C.
9 mg was obtained.

NMR (CDCl 3 +DMSO-dt) Near, 5
4(IH,s), 6.79(3)1°s), 5.9~
5.4 (LH, m), 4.74 (211, s), 4.4
9, 4.39 (total 2H, each s), 3.82 (611
,s).

Mass (m/e): 353 (M ""), 3
18,151 (100χ) Example 5 4-chloro-5-(3,4-dimethoxybenzylamino)-2-(2-N,N-dimethylaminoethyl)-3(
311) Pyridazinone hydrochloride (compound 9) 4-chloro-5-(3,4-dimethoxybensylamino)-2-(2-N,N-dimethylaminoethyl)-3(2H ) To a mixture of pyridazinone 150■ and chloroborum 10IlIN, add 6N 11C under ice-cooling.
Fl,4-dioxane solution 21 was added, and after being left at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The resulting residue was mixed with 5n of water.
The filtrate was lyophilized to obtain 120 mg of the title compound as hygroscopic yellow crystals.

Example 6 4-chloro-5-(3-n-pentyloxy-4-methoxybenzylamino)-2-(2-carboxyethyl)
-3(2H)pyridazinone 4.5-dichloro-2-(2-carboxyethyl) -
3(211)pyridazinone 400■, 3-n-pentyloxy-4-methoxybenzylamine hydrochloride 1.49g
, potassium carbonate 1.05 g, 1,4-dioxane 5
mj2 and 15 ml of water were refluxed for 8 hours with stirring. 1.
4-Dioxane was distilled off under reduced pressure, and the residue was extracted with chloroborm. The extract was washed with dilute hydrochloric acid and water in that order, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) as a pale yellow viscous oil with the title title Compound 250■
I got it.

NMR (CDCIt 3) δ near, 59 (18,s
), 6.83 (311,s), 5.44(I
ll, brs), 4.50.4.44 (21. each s in total), 4.40-3.50 (6t1.m)
, 3.83 (38,s) , 2.10~1.1
0 (611, m), 0.93 (311, t).

Mass (m/e): 395 (M''), 3
60.207 (100χ), 137° Example 7 4-Promo5-(3-n-pentyloxy-4-methoxybenzylamino)-3(2+1) Pyridazinone 4.5-Dibromo-3(211) Pyridazinone 1. 5
2g.

7.5 tl of 4.01 g of 3-n-pentyloxy-4-methoxybenzylamine and 60 ml of ethanol with stirring
Distant flow was carried out for l. Ethanol was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate. Dilute the extract with dilute hydrochloric acid.

After washing with water and drying with sodium sulfate, the solvent was distilled off.
The resulting residue was crystallized from ethyl acetate-diethyl ether to obtain 1.42 g of the title compound as pale yellow crystals with a melting point of 148-150'C.

N? 1R (CDCIt,) δ near, 51 (IH, s),
6.82 (3H, s), 5.28 (III, brs)
, 4.5L 4.41 (total 2H, each s),
3.97 (28°t), 3.84 (3H, s), 2.0
5-1.05 (6H, m), 0.96 (38, t).

Mass (m/e): 395 (M, 316 (100)
χ), 207,137° Table 1 shows examples of compounds synthesized according to the above examples. In the rightmost column of the table, the number of the Example applied mutatis mutandis is written.

(Hereinafter, blank space) Formulation Examples 1 and 2 Tablet Compound 11h2 or Compound Floor 38 10g Milk Fi2
0 g starch 4 g starch (for glue) 1 g magnesium stearate 100 μ total amount 42.1 g The above ingredients were mixed in a conventional manner to form sugar-coated tablets containing 50 μ of the active ingredient in each tablet.

Formulation Examples 3 and 4 Capsule Compound Na3 or Compound Na32 10g Lactose
20g microcrystalline cellulose 10g magnesium stearate 1g total ffi 4
1 g of the above ingredients were mixed in a conventional manner and then filled into gelatin capsules to yield capsules containing 50 μ of active ingredient per capsule.

Formulation Examples 5 and 6 Soft capsule Compound N [L12 or Compound N [L39 Log corn oil 35 g total amount
45g After mixing the above ingredients, soft capsules were prepared by a conventional method.

Formulation Examples 7 and 8 Ointment Compound 11ih13 or Compound m41 1.0 g Olive oil 20 g White petrolatum
79g total amount 100g The above ingredients were mixed in a conventional manner to prepare a 1% ointment.

Formulation Examples 9 and 10 Aerosol Suspension (A) Compound No 2 or Compound &37 0.25% Isopropyl myristate 0.10 Ethanol
26.40CB) The above composition (Δ) was mixed, the resulting mixed solution was charged into a container equipped with a valve, and the propellant (B) was heated to about 2.4
It was press-injected through a valve nozzle to a gauge pressure of 6 to 2.81 kg/crA to obtain an aerosol suspension.

Claims (1)

[Claims] 1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R_1 is a hydrogen atom, a methyl group, an alkenyl group having 3 to 6 carbon atoms, or a carbon number 5 or 6 cycloalkyl group, benzyl group, phenyl group, -(CH_2)m-CO_2R_3 (R_3 means a hydrogen atom or a C1-C5 alkyl group, m is 1
means an integer between 4 and 4. ), -(CH_2)n-A
[A means OH or -N(R_4)_2 (R_4 means an alkyl group having 1 to 3 carbon atoms), and n means an integer of 2 to 6. ] or -CH_2CF
_3; R_2 means a chlorine atom or a bromine atom; Y_1 and Y_2 are the same or different; each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, and 2 carbon atoms;
-8 alkenyl group, halogen atom, -OR_5 [
R_5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a numerical formula, chemical formula, table, etc. (q means an integer from 1 to 4). -CO_2R_6 (R_6 means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), -N(R
_7)_2 (R_7 means an alkyl group having 1 to 4 carbon atoms) or -SR_8 (R_8 means an alkyl group having 1 to 4 carbon atoms); Y_3 means an alkyl group having 1 to 5 carbon atoms. Alkyl group, alkenyl group having 2 to 8 carbon atoms, halogen atom, -OR_5 (R_5 has the same meaning as above), -CO_2R_6 (R_6
has the same meaning as the above explanation. ), -N(R_7)_
2 (R_7 has the same meaning as in the above explanation) or -
SR_8 (R_8 has the same meaning as in the above explanation). } and, if possible, pharmaceutically acceptable salts thereof. (2) General formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_1 is a hydrogen atom, a methyl group, an alkenyl group having 3 to 6 carbon atoms, or a cycloalkyl group having 5 or 6 carbon atoms. group, benzyl group, phenyl group, -(CH_2)m-CO_2R_3 (R_3 means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, m is 1
means an integer between 4 and 4. ), -(CH_2)n-A
[A means OH or -N(R_4)_2 (R_4 means an alkyl group having 1 to 3 carbon atoms), and n means an integer of 2 to 6. ] or -CH_2CF
_3 means; R_2 means a chlorine atom or a bromine atom; Z means a chlorine atom or a bromine atom. ) and the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, Y_1 and Y_2 are the same or different and each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, C2-C8 alkenyl group, halogen atom, -OR_
5 [R_5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a numerical formula, chemical formula, table, etc. (q means an integer from 1 to 4)]. -CO_2R_6 (R_6 means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), -N(R
_7)_2 (R_7 means an alkyl group having 1 to 4 carbon atoms) or -SR_8 (R_8 means an alkyl group having 1 to 4 carbon atoms); Y_3 means an alkyl group having 1 to 5 carbon atoms. Alkyl group, alkenyl group having 2 to 8 carbon atoms, halogen atom, -OR_5 (R_5 has the same meaning as above), -CO_2R_6 (R_6
has the same meaning as the above explanation. ), -N(R_7)_
2 (R_7 has the same meaning as in the above explanation) or -
SR_8 (R_8 has the same meaning as in the above explanation). ) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1, R_2, Y_1, Y_2 and Y_3
has the same meaning as the above explanation. ] A method for producing a pyridazinone derivative represented by (3) General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R_1 is a hydrogen atom, a methyl group, an alkenyl group having 3 to 6 carbon atoms, or a cycloalkyl group having 5 or 6 carbon atoms. group, benzyl group, phenyl group, -(CH_2)m-CO_2R_3 (R_3 means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, m is 1
means an integer between 4 and 4. ), -(CH_2)n-A
[A means OH or -N(R_4)_2 (R_4 means an alkyl group having 1 to 3 carbon atoms), and n means an integer of 2 to 6. ] or -CH_2CF
_3; R_2 means a chlorine atom or a bromine atom; Y_1 and Y_2 are the same or different; each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, and 2 carbon atoms;
-8 alkenyl group, halogen atom, -OR_5 [
R_5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or ▲a numerical formula, a chemical formula, a table, etc.▼(q means an integer from 1 to 4)], - CO_2R_6 (R_6 means a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), -N(R
_7)_2 (R_7 means an alkyl group having 1 to 4 carbon atoms. Or -SR_8 (R_8 means an alkyl group having 1 to 4 carbon atoms); Y_3 is an alkyl group having 1 to 5 carbon atoms. group, alkenyl group having 2 to 8 carbon atoms, halogen atom, -OR_5 (R_5 has the same meaning as above), -CO_2R_6 (R_6 has the same meaning as above), -N(R_7 )_2 (R_7 has the same meaning as in the above explanation.) or -SR_8 (R
_8 has the same meaning as the above explanation. ) means. }
An anti-allergic agent characterized by containing a pyridazinone derivative represented by and, if possible, a pharmaceutically acceptable salt thereof.